Abstract
B. anthracis is a bioweapon of primary importance and its pathogenicity depends on its lethal and edema toxins, which belong to the A-B model of bacterial toxins, and on its capsule. These toxins are secreted early in the course of the anthrax disease and for this reason antibiotics must be administered early, in addition to other limitations. Antibodies (Abs) may however neutralize those toxins and target this capsule to improve anthrax treatment, and many Abs have been developed in that perspective. These Abs act at various steps of the cell intoxication and their mechanisms of action are detailed in the present review, presented in correlation with structural and functional data. The potential for clinical application is discussed for Abs targeting each step of entry, with four of these molecules already advancing to clinical trials. Paradoxically, certain Abs may also enhance the lethal toxin activity and this aspect will also be presented. The unique paradigm of Abs neutralizing anthrax toxins thus exemplifies how they may act to neutralize A-B toxins and, more generally, be active against infectious diseases.
Highlights
Anthrax is caused by the gram-negative, spore forming bacterium Bacillus anthracis
Recombinant Abs against anthrax were actively developed because Abs of animal origin had previously been shown to increase that window, in animal models of the disease, and shortened the duration of antibiotherapy. Those animal Abs were directed against anthrax toxins, which were targeted by recombinant Abs, isolated at a time when the structures of these toxins have been resolved
This competition explains that Ab concentration plays a role in toxin neutralization, as it relies on a dynamic equilibrium
Summary
Anthrax is caused by the gram-negative, spore forming bacterium Bacillus anthracis. This lethal disease is still endemic in some parts of the world, primarily to herbivores in the less-developed countries but can affect a wide range of species, including humans. Domain II (residues 259–487) is involved in heptamer and pore formation, and interacts with anthrax toxin receptors (ATRs) [9,10]. Antibiotics have replaced the Abs as main molecules for anthrax treatment but they have limitations which, in turn, may be compensated by Abs. In effect, current antimicrobials (fluoroquinolone, tetracycline or penicillin G) [22,23] require early administration in order to provide protection, due to the rapid course of infection and toxins secretion after exposure to B. anthracis spores by the pulmonary route. Abs are generally expected to increase the therapeutic window, decrease the length of treatment, and overcome potential antibiotic resistant strains Abs enabling these functions, by targeting the pathogenic mechanisms at various steps involving LT/ET toxicity, will be reviewed in this article. The scope of the manuscript is not to correlate Abs and vaccination, but rather how monoclonal and recombinant Abs act
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